A comprehensive program has been outlined for evaluating the therapeutic potential of the carboxylic ionophores and establishing the elements of their multifaceted mechanism of action on intact animals as well as the isolated perfused heart. The principal cardiovascular effects of a variety of naturally produced and biosynthetically modified ionophores, (1) positive inotropy and (2) coronary vasodilation, will be characterized in depth in several animal systems including intact instrumented dogs ("low K ion erythrocytes) and sheep ("high K ion erythrocytes). The cardiovascular effects of ionophores upon the syndrome of endotoxic shock will be studied as well as their effects on the survival of dogs and rats in shock. The isolated rabbit heart, perfused at constant rate in order to read out coronary resistance as a continual function, will be utilized extensively to establish the role of adenosine release in ionophore-mediated coronary vasodilitation and pO2-mediated coronary flow-autoregulation. The effect of ionophores and other drugs on the hydraulic work efficiency will also be examined on the isolated heart system and compared to analagous effects in instrumented dogs. New ionophores will be synthesized in a systematic fashion and characterized with respect to various biophysical parameters in a rational effort to develop new drugs with superior cardiovascular properties. Particular attention will be focused on the evaluation of the degree of current exposure of man to the potent cardiotrophic ionophores entering his food supply in the form of farm animal feed supplements.